Oral Progestin Research Articles

Porcine endometrial heat shock proteins are differentially influenced by pregnancy status, heat stress, and altrenogest supplementation during the peri-implantation period.

Heat stress (HS) deleteriously affects multiple components of porcine reproduction and is causal to seasonal infertility. Environment-induced hyperthermia causes a HS response (HSR) typically characterized by increased abundance of intracellular heat shock proteins (HSP). Gilts exposed to HS during the peri-implantation period have compromised embryo survival, however if (or how) HS disrupts the porcine endometrium is not understood. Study objectives were to evaluate the endometrial HSP abundance in response to HS during this period and assess the effect of oral progestin (altrenogest; ALT) supplementation. Postpubertal gilts (n = 42) were artificially inseminated during behavioral estrus (n = 28) or were kept cyclic (n = 14), and randomly assigned to thermal neutral (TN; 21 ± 1 °C) or diurnal HS (35 ± 1 °C for 12 h/31.6 ± 1 °C for 12 h) conditions from day 3 to 12 postestrus (dpe). Seven of the inseminated gilts from each thermal treatment group received ALT (15 mg/d) during this period. Using quantitative PCR, transcript abundance of HSP family A (Hsp70) member 1A (HSPA1A, P = 0.001) and member 6 (HSPA6, P < 0.001), and HSP family B (small) member 8 (HSB8, P = 0.001) were increased while HSP family D (Hsp60) member 1 (HSPD1, P = 0.01) was decreased in the endometrium of pregnant gilts compared to the cyclic gilts. Protein abundance of HSPA1A decreased (P = 0.03) in pregnant gilt endometrium due to HS, while HSP family B (small) member 1 (HSPB1) increased (P = 0.01) due to HS. Oral ALT supplementation during HS reduced the transcript abundance of HSP90α family class B member 1 (HSP90AB1, P = 0.04); but HS increased HSP90AB1 (P = 0.001), HSPA1A (P = 0.02), and HSPA6 (P = 0.04) transcript abundance irrespective of ALT. ALT supplementation decreased HSP90α family class A member 1 (HSP90AA1, P = 0.001) protein abundance, irrespective of thermal environment, whereas ALT only decreased HSPA6 (P = 0.02) protein abundance in TN gilts. These results indicate a notable shift of HSP in the porcine endometrium during the peri-implantation period in response to pregnancy status and heat stress.

P-700 Oral progestins are a good alternative to traditional antagonists in freeze all IVF cycles yielding comparable mature oocyte rate and viable embryo number

Abstract Study question May oral progestins be a good alternative to traditional antagonists in freeze all cycles and yield comparable number of mature oocytes and viable embryos? Summary answer Oral progestins are an effective alternative to antagonists in preventing premature ovulation in freeze all cycles, are more patient friendly and have a lower cost. What is known already Progestine-primed ovarian stimulation (PPOS) protocols are new protocols available for the last 5-6 years that proved to be effective in preventing premature LH surge. A recent meta-analysis by Shaogen Guan et al. including 9 studies with 1885 cycles showed that PPOS is an effective ovarian stimulation protocol and may be an alternative to antagonist in planned freeze all in vitro fertilization (IVF) cycles. Study design, size, duration Our study is retrospective cross sectional self-controlled study. We compared 2 groups of patients with 150 patients in each group undergoing IVF treatment for the period from September 2019 to November 2021 in our centre. Participants/materials, setting, methods We used oral dydrogesterone 20 mg a day from the first day of stimulation in progestine group and started cetrorelix 0.25 mg after having 2 follicles &amp;gt; 12 mm in antagonist group. "Freeze all" strategy was applied in progestine group. In antagonist group patients underwent either "freeze all" or fresh transfer. Patients aged 21-34, with antral follicle count &amp;gt; 10 were included. Patients with endometriomas and poor oocyte quality on the previous cycles were excluded. Main results and the role of chance Mean age of patients in dydrogesterone group was 27,9 and in antagonist group - 27,3. We used recombinant follicle stimulating hormone (rFSH) in patients younger than 30 years of age and combined it with human menopausal gonadotropin (HMG) in patients older than 30. For final oocyte maturation decapeptyl was used in progesterone group and either decapeptyl or human chorionic gonadotropin in antagonist group. Mean amount of rFSH used for one cycle in dydrogesterone group was 1726 IU and HMG 562,5 IU; in antagonist group 2013,7 and 665.6 IU respectively. There was no noticeable difference between total number of retrieved oocytes and in maturity rate. Mean number of retrieved oocytes was 18,3 in dydrogesterone group and 17,1 in antagonist group (p = 0.138). Mean number of mature oocytes were 13,4 (73,2%) and 13,1 (76,1%) in dydrogesterone and antagonist groups respectively (p = 0.131). We also didn't find significant difference in number of viable embryos on the day 3: 7,9 in dydrogesterone group and 8.3 in antagonist group (p = 0,321). As a secondary outcome we looked at ongoing pregnancy rate and there was also no significant difference between two groups. This number was 37,5 % in PPOS group and 35,6 % in antagonist group (p = 0,335). Limitations, reasons for caution We didn't exclude patients with severe male factor which might influence our secondary outcome. Patients with polycystic ovarian syndrome (PCOS) were included in the study mainly in the dydrogesterone group, it is known that in these patients maturity problems may happen. Use of different trigger agents may put some limitations. Wider implications of the findings We showed in our study that PPOS protocols are not inferior to traditional antagonist protocol. These protocols are more patient-friendly because of less number of injections and probably less number of ultrasound folliculometry as well as lower cost. Tablets are easy to take and patient compliance is good. Trial registration number not applicable

O-130 Reproductive outcomes of normal ovarian reserve patients after progestin-primed ovarian stimulation with chlormadinone acetate vs GnRH antagonist: A retrospective study with inverse-probability-of-treatment weighting

Abstract Study question To evaluate the effectiveness of chlormadinone acetate (CMA) for preventing premature LH surge in patients with normal ovarian reserve compared to cetrorelix. Summary answer In progestin-primed ovarian stimulation (PPOS) than GnRH antagonist (GnRH-ant), the incidence of premature LH surge was significantly lower, without significant difference in oocyte maturation rate. What is known already The GnRH-ant protocol is one of the conventional protocols which has some disadvantages including increased premature LH surge rate and cancelation rate. In recent years, the PPOS protocol has attracted attention as a new ovarian stimulation using progestin as an alternative to GnRH analog for suppressing a premature LH surge, however its efficacy is still controversial. In addition, many studies have investigated the reproductive outcomes of PPOS using medroxy-progesterone acetate or dydrogesterone; however, there are few reports of CMA, an oral progestin, which is inexpensive and widely used in Japan. Study design, size, duration This retrospective cohort study was performed in a reproduction center between March 2018 and October 2020 which included 977 Japanese patients with normal ovarian reserve undergoing PPOS with CMA (n = 299), or GnRH antagonist (GnRH-ant) with cetrorelix (n = 608) in their first IVF cycle at the reproduction center. In subgroup analysis, pregnancy outcomes after frozen embryo transfers (FET) between PPOS (n = 284) and GnRH-ant (n = 579) were also compared. Participants/materials, setting, methods The inclusion criteria were patients aged &amp;lt; 40 years and AMH ≧ 1.1 ng/mL, who underwent autologous oocyte retrieval in their first IVF cycle with freeze-all strategy. The primary outcome was the incidence of premature LH surge, the secondary outcomes was oocyte maturation rate. To reduce the impact of treatment bias and potential confounding factors, we conducted logistic regression models with inverse-probability-of-treatment weighting (IPTW). Main results and the role of chance After IPTW, baseline clinical data were well-balanced between the two groups, including age, AMH, BMI, the duration, type, and cause of infertility, antral follicle count, the history of recurrent spontaneous abortion, and previous IVF attempts. The premature LH surge rate was significantly lower with PPOS (3.1%) compared to GnRH-ant (20.1%) (odds ratio, 0.21; 95% confidence interval, 0.11–0.36). No significant differences were found in total gonadotropin dose (2400IU for PPOS vs 2400IU for GnRH-ant, p = 0.136), the number of oocyte retrieval (n = 15 vs n = 15, p = 0.484), oocyte maturation rate (78.8% vs 77.8%, p = 0.275), fertilization rate (73.0% vs 72.0%, p = 0.412), viable embryo rate per oocyte retrieval (40% vs 40%, p = 0.890), and good quality blastocyst rate (72.0% vs 69.6%, p = 0.092). However, the good quality day-3 embryo rate was significantly lower with PPOS (37.2% vs 49.1%, p &amp;lt; 0.05). There were no differences in the incidence of moderate-to-severe OHSS (0.3% vs 0.7%, p = 0.481). In FET cycles, the pregnancy outcomes, such as implantation rate (43.1 % vs 51.9 %, p = 0.013) and clinical pregnancy rate (46.5% vs 54.7%, p = 0.027) were significantly lower with PPOS, however, no significant differences were found in ongoing pregnancy rate (75.6% vs 80.5%, p = 0.325), and live birth rate (72.4% vs 79.5 %, p = 0.142). Limitations, reasons for caution This was a retrospective cohort study conducted in a single center. The participants in this study were limited to Japanese ethnicity. The results need to be validated across different centers and other ethnicities. Wider implications of the findings This is the first report assessing the reproductive outcomes on PPOS using CMA, widely used in Japan. The PPOS with CMA significantly suppressed the premature LH surge rate compared to GnRH-ant protocol, without decrease in oocyte maturation rate. Trial registration number N/A

P-578 Oral, Vaginal or Intramuscular Progesterone in Programmed Frozen Embryo Transfer Cyles: A Pilot RCT

Abstract Study question What should be the optimal luteal phase support in programmed frozen embryo transfer (FET) cycles using vitrified-thawed blastocysts? Summary answer 40mg/day oral dydrogesterone, 180mg/day progesterone (P) vaginal gel and 100mg/day im P in oil revealed similar reproductive outcomes in programmed FET cycles. What is known already Luteal phase should be supported either in fresh (Yanushpolsky et al, 2015) or in FET cycles (Pabuccu et al, 2020). Endometrium preparation in FET cycles is outmost important for successful implantation. For this purpose, natural or programmed protocols have been suggested. In programmed FET cycles, exogenous P replacement is of critical importance, as estrogen use will inhibit ovulation and corpus luteum formation.Higher serum P level was associated with increased rates of ongoing pregnancy or live birth in programmed FET cycles (Melo et al 2021). Therefore, lack of a corpus luteum justifies precise and adequate luteal support. Study design, size, duration This was a randomized, parallel, phase IV-pilot RCT (NCT03948022), comparing 3 different luteal support options in programmed FET cycles. A total of 168 women aged between 20-40 years and having available blastocyst(s) were eligible for the study between April-December 2020. After excluding cases, 163 patients were randomly assigned to one of the P arms based on a computer- generated list to administer: 1-oral dydrogesterone 40mg/day (DYD) 2-vaginal %8 P gel 180mg/day (VAG) 3-im 100mg/day P (IM) Participants/materials, setting, methods Estradiol 2 mg TID was started on day 2 or 3 of menstruation for at least 7 days. On day 8, endometrial thickness was assessed. When it was &amp;gt;8 mm, each patient was randomly assigned to one of the intervention arms. After 5 days of P administration, ET was performed on the 6th day preceding serum P measurement. Primary outcome was ongoing pregnancy rate defined as viable healthy pregnancy beyond 20th week of gestation. Main results and the role of chance A total of 151 women out of 163 completed the primary follow-up after randomization. 12 patients were excluded from the final analysis mainly due to protocol violation and discontinuation of intervention. Each patient contributed to a single cycle in the analysis and given data does not include cumulative pregnancies including surplus frozen embryo transfers. Demographic data including; mean woman age, body mass index, serum AMH, TSH and infertility etiologies were comparable among all groups without statistically significance (p &amp;gt; 0.5) Limitations, reasons for caution Lack of a power analysis is the main limitation of this study, potentially coming with type-1 error. Properly designed and powered RCTs are needed. Wider implications of the findings There have been very limited data available for oral progestogen use particularly in FET cycles, unlike many reports for vaginal and im P. Comperable reproductive outcomes with significantly lower side effect profile of oral progestagen merits further attention in programmed FET cycles. Trial registration number NCT03948022

Surgical window-of-opportunity study of megestrol acetate compared with megestrol acetate and metformin for endometrial intraepithelial neoplasia.

TPS5601 Background: Endometrial Intraepithelial Neoplasia (EIN) is a precursor lesion to endometrial carcinoma (EC), the most common gynecologic cancer among women in the US. The current standard of care for women with EIN is hysterectomy. Non-surgical treatments are needed for women desiring fertility preservation, and for those who are medically unfit for a major surgical procedure. Progestin therapy is the cornerstone of current nonsurgical management of EIN. However, approximately 30% of patients with EIN do not respond to progestin therapy, or respond incompletely. EIN is closely related to insulin resistance and metabolic syndrome with evidence that increased insulin resistance is a significant risk factor for development of EC. Metformin, an inhibitor of insulin/PI3K/AKT pathway, has been demonstrated to reduce endometrial proliferation in vitro and in vivo. We hypothesize that the combination of metformin and progestin therapy may synergize to arrest EIN progression and prevent the development of EC. Methods: This is a randomized pre-surgical window of opportunity study, comparing a commonly used oral progestin, megestrol acetate (MA), to MA and metformin (M). Patients with pathologically confirmed EIN or complex atypical hyperplasia (CAH) who present for hysterectomy will be approached. After enrollment, participants will receive MA 80mg PO BID ± M 500mg BID for 4 ± 1 weeks pre-operatively. Post-therapy endometrial biopsy will be obtained in the operating room prior to the hysterectomy, and compared to the pre-therapy diagnostic endometrial biopsy sample. The primary endpoint is the change in the percentage (%) of Ki-67 expressing cells (%Ki-67) between the pre- and post-treatment biopsies. Based on a two-sample t-test comparing the pre- to post-treatment changes in %Ki-67 between the two arms, a sample size of 21 patients per arm achieves 80% power with two-sided α = 0.05 to detect an absolute reduction in %Ki-67 of 10% vs. 17.6% in the MA vs. MA + M arms. An interim analysis is planned after enrollment of 32 patients, and an internal pilot approach based on variance re-estimation will be used to increase the sample size if needed, to maintain the original planned power. Secondary endpoints will include comparison of changes in protein expression of ER, PR, PTEN/PAX2, markers of the PI3K/AKT/MTOR pathway, cell death and intratumoral insulin signaling. We will randomize 50 subjects at five sites: Northwestern University, Cedars-Sinai (Los Angeles), Duke University, University of Colorado, and University of North Carolina. Participants will be randomized 1:1 and stratified by menopausal status to ensure balance between the two arms. Since September 2021, four sites have opened and 22 patients have been pre-screened. Three participants were enrolled and two have completed intervention. The study is expected to complete accrual by the end of 2023. Clinical trial information: NCT04576104.

031 Medical and surgical management of endometriosis in teenagers

Menstrual symptoms such as dysmenorrhea are frequently reported, both in adults as in the adolescent population. A significant number of high school students report missed school days due to menstrual symptoms. Endometriosis is associated with painful menstruation and chronic pelvic pain. It’s true prevalence in the adolescent population is unknown, although 2/3rds of laparoscopies performed for pelvic pain in adolescents show endometriosis. Before discussing treatment, it is vital that severe menstrual pain is not regarded as normal, and should warrant further medical advice (which may include ultrasound) in case it has an impact on school and social activities, to reduce diagnostic and treatment delay. Treatment of endometriosis-associated pain may be medical and/or surgical, although data in the adolescent population are scarce. First line medical treatment can be offered with NSAIDs, and where appropriate hormonal treatment such as combined oral contraceptives or progestogens. Although GnRH-analogues have shown to be effective for pain treatment, they should be used very restrictively and with great caution due to their side effects and reduction of (peak) bone mineral density. Surgical treatment can be offered in case of pain not responding to hormonal treatment, or in case large cysts or bowel/ureter obstruction is found. Laparoscopy should be performed by an experienced team, to avoid repeat surgery and its associated risks. Postoperative hormonal treatment is advised to reduce recurrence rates.

Interventions for heavy menstrual bleeding; overview of Cochrane reviews and network meta-analysis.

Interventions for heavy menstrual bleeding; overview of Cochrane reviews and network meta-analysis.

Implementation of a pharmacist-led hormonal contraceptive prescribing service in a campus community pharmacy in Indiana, United States

Objective(s)College-age people have the highest numbers of unintended pregnancies and pharmacies within college campuses are in a unique position to meet student needs. Our objective was to implement a pharmacist contraceptive prescribing service in a campus pharmacy and examine the service utilization. Study designThe Purdue University Pharmacy (Indiana, United States) implemented a pharmacist hormonal contraception prescribing service via a collaborative drug therapy management agreement with the campus student health center. The collaborative drug therapy management agreement enables pharmacists to independently prescribe pills, patches, rings, injections, and emergency contraception to students meeting eligibility criteria. After completing a patient health screening and blood pressure check, the pharmacist discusses the eligible method(s) and prescribes up to a 12-month supply. A referral to another provider for long-acting reversible contraception or further evaluation may also be provided. We collected basic information about each encounter (e.g., age, blood pressure, method of contraception prescribed, and time). ResultsDuring the 2020–2021 academic year, 125 prescribing consultations took place with an average appointment length of 20 minutes (range, 12–65 minutes). The median patient age was 21 years (range, 18–30 years). Eligible patients (n = 123, 98%) received a prescription and 119 (95%) prescriptions were written: combined oral pill (n = 91, 77%), injection (n = 12, 10%), patch (n = 6, 5%), vaginal ring (n = 5, 4%), and progestin only pill (n = 5, 4%). Conclusion(s)The pharmacist contraception prescribing service developed by the Purdue University Pharmacy and Student Health Center is a unique approach to meeting the needs of students. Few external resources are required for implementation, and most patients were medically eligible to receive hormonal contraception. ImplicationsCollaboration between on-campus student health centers and pharmacies can be explored as 1 approach to increase access to hormonal contraception for students.

Randomized study on the effectiveness of nomegestrol acetate plus 17β-estradiol oral contraceptive versus dienogest oral pill in women with suspected endometriosis‑associated chronic pelvic pain

BackgroundTo evaluate the effects of a combined oral contraceptive containing 1.5 mg 17b-estradiol (E2) and 2.5 mg nomegestrol acetate (NOMAC) or 2 mg/daily dienogest (DNG) oral progestin on endometriosis-associated chronic pelvic pain (CPP) and on the quality of life (QoL) and sexual function, by a randomized study design.MethodsThe E2/NOMAC group and DNG group included 99 and 98 women, respectively. The levels of CPP were measured by the visual analogic scale (VAS). The QoL scores were investigated by the Short Form-36 questionnaire (SF-36). Finally, sexual function was studied using the Female Sexual Function Index (FSFI), while sexual distress was studied by the Female Sexual Distress Scale (FSDS). The study had 3, 6 and 12-month follow-ups.ResultsThe intra-group analysis showed an improvement of the VAS score from baseline to the 12-month follow-up in the women of both groups (p < 0.001). The inter-group comparison showed a similar improvement of CPP (p = 0.06). Women on DNG had better SF-36 somatic (p < 0.01) and FSFI scores (p < 0.006) than women on E2/NOMAC at the 6- and 12-month follow-ups.ConclusionsThe results support the efficacy of both hormonal treatments, even if DNG was more effective than E2/NOMAC in a limited intergroup comparison.

Method of Hormonal Contraception and Protective Effects Against Ectopic Pregnancy.

To estimate the incidence rates for ectopic pregnancy by contraceptive method in a cohort of women using hormonal contraception in Sweden between 2005 and 2016. Women aged 15-49 years with a filled prescription for a hormonal contraceptive in the Swedish Prescribed Drug Register between 2005 and 2016 were included. For each woman, all exposed woman-years were allocated to treatment episodes depending on the method of contraception. Treatment time started on the day the prescription was filled and ended on the first day of the end of supply, new eligible dispensing, pregnancy-related diagnosis and its associated estimated last menstrual period, or removal procedure. Ectopic pregnancy was defined as having at least two records of International Classification of Diseases, Tenth Revision code O00-, including O00.0, O00.1, O00.2, O00.8, O00.9, within 30 days or one episode of O00- and one surgical procedure for ectopic pregnancy (NOMESCO Classification of Surgical Procedures code LBA, LBC, LBD, LBE, LBW). Incidence rates per 1,000 woman-years and 95% CIs were calculated for each method of contraception. The study included 1,663,242 women and 1,915 events of ectopic pregnancy. The incidence rate (95% CI) for ectopic pregnancy per method of hormonal contraception was estimated: 13.5-mg levonorgestrel (LNG) hormonal intrauterine device (IUD), 2.76 (2.26-3.35) per 1,000 woman-years; 52-mg LNG hormonal IUD, 0.30 (0.28-0.33) per 1,000 woman-years; combined oral contraception, 0.20 (0.19-0.22) per 1,000 woman-years; progestogen implants, 0.31 (0.26-0.37) per 1,000 woman-years; oral medium-dose progestogen (desogestrel 75 mg), 0.24 per 1,000 woman-years, (0.21-0.27); and oral low-dose progestogen (norethisterone 0.35 mg and lynestrenol 0.5 mg), 0.81 (0.70-0.93) per 1,000 woman-years. Hormonal contraception lowers the risk of ectopic pregnancy markedly. The incidence rate of ectopic pregnancy among women using a low-dose hormonal IUD (13.5 mg LNG) was substantially higher than that in women using other types of hormonal contraception. This study provides real-world evidence to inform best clinical practice for women-centered contraceptive counseling.

Evaluation and management of acute abnormal uterine bleeding in adolescents: oral contraceptive pill taper versus single-dose therapy, a pilot study

Background: Hormonal management is first-line therapy for acute abnormal uterine bleeding (AUB) in adolescents. Studies have demonstrated efficacy of oral contraceptive pill (OCP) and progestin tapers and single dose therapy for acute AUB, but comparative studies, side effects and patient satisfaction rates are lacking. Our objective was to implement QI measures to standardize evaluation of acute AUB and prospectively assess time to amenorrhea, patient satisfaction and side effects in teens treated with OCP taper versus single-dose OCP and progestin.

111 Megestrol acetate therapy and secondary adrenal insufficiency in a patient with complex atypical hyperplasia

Introduction: Complex atypicalendometrialhyperplasiasuggestsasignificantpre‐malignantstate ofendometrialcarcinoma, and tends to occur at a young age. Oral progestins have been used as conservative treatment in young women with atypical endometrial hyperplasia who want to preserve their fertility combined with levonorgestrel‐releasing intrauterinesystem (Mirena). Method: A 37 obese nulliparous woman, with a history of insulin resistance treated with metformin, presented with symptoms of menorrhagia for over than 5 years.

Abstract P131: Cerebral Venous Sinus Thrombosis Risk Factors, Treatments, And Sequelae: 2011-2019

Introduction: Cerebral venous sinus thrombosis (CVST) is a rare but potentially debilitating thrombosis affecting 3-4 cases per million adults in the United States. Risk factors are thought similar to venous thrombosis, but there is little epidemiologic data corroborating this assertion. Concern about a possible association between the Janssen (Johnson and Johnson) and Oxford-AztraZenaca COVID-19 vaccines and cases of CVST resulted in increased global attention to this condition. Thus, large epidemiological assessment of the risk factors, treatment and outcomes of CVST are needed. Objective: Estimate the distributions of risk factors antecedent to CVST diagnosis, report CVST treatments in clinical practice, and potential sequelae of CVST in a large retrospective cohort of adults with CVST in the United States. Methods: MarketScan Commercial and Medicare Supplemental administrative databases were employed to assess CVST diagnosed between 2011 and 2019 in the U.S. Validated International Classification of Disease (ICD) codes and receipt of an outpatient anticoagulant (either oral or subcutaneous anticoagulant) prescription within 30 days of the ICD code identified incident CVST. Antecedent clinical characteristics, treatments, and sequelae of CVST were identified using inpatient, outpatient, and prescription data. For outcomes, proportions and incidence with 95% confidence intervals (CIs) were calculated, stratified by sex. Results: We identified 1,869 CVST patients. Of these 1,314 (70%) were female, with 200 (10%) events identified as a pregnancy-related CVST. The average age was 41 years for females and 48 years for men. Among women, 24.7% were on hormonal therapy (oral contraceptive, estrogen, and progestin) prior to diagnosis. Men had a higher prevalence of comorbidities, such as diabetes (15% men vs. 9% women) and cancer (19% men vs. 10% women). Oral anticoagulant (OAC) use was the most common treatment for CVST in both men (88%) and women (85%) and did not vary by sex. Use of procedures to treat CVST, optic nerve fenestration and catheter directed thrombolysis, were 0.5% and 4.1%, respectively. The most common sequela after CVST was incidence of intracranial hypertension (Incidence: 4.2 per 100 person-years; 95% CI: 3.3, 5.1) and palliedema was rare. Conclusions: Overall, a majority of CVST patients were women of reproductive age. Our findings suggest a potential association with both endogenous (pregnancy) and exogenous (oral contraceptives, HRT) hormones which needs further study. In our sample, CVST was managed with oral anticoagulants, regardless of sex, and intracranial hypertension was elevated following CVST. This large claims-based analysis is a descriptive insight into the risk factors and management of CVST, a rare and debilitating condition.

Fertility-Sparing Approaches in Atypical Endometrial Hyperplasia and Endometrial Cancer Patients: Current Evidence and Future Directions.

Endometrial cancer (EC) is the fourth most common cancer in women in developed countries. Although it is usually diagnosed in postmenopausal women, its incidence has increased in young women, as well in recent decades, with an estimated rate of 4% in those under 40 years of age. Factors involved in this increase, particularly in resource-rich countries, include delayed childbearing and the rise in obesity. The new molecular classification of EC should help to personalize treatment, through appropriate candidate selection. With the currently available evidence, the use of oral progestin either alone or in combination with other drugs such as metformin, levonorgestrel-releasing intrauterine devices and hysteroscopic resection, seems to be feasible and safe in women with early-stage EC limited to the endometrium. However, there is a lack of high-quality evidence of the efficacy and safety of conservative management in EC. Randomized clinical trials in younger women and obese patients are currently underway.

Progesterone: A Unique Hormone with Immunomodulatory Roles in Pregnancy.

Progesterone is well known for its numerous endocrinologic roles in pregnancy but is also endowed with fascinating immunomodulatory capabilities. It can downregulate the induction of inflammatory reactions, the activation of immune cells and the production of cytokines, which are critical mediators of immune responses. These features appear to be critical to the success of pregnancy, given the ability of maternal immune reactivity to interfere with pregnancy and to contribute to several pregnancy complications. This review summarizes the contribution of maternal immune effectors in general, and cytokines in particular, to pregnancy complications such as recurrent miscarriage, pre-eclampsia and preterm labor; it describes the promise offered by supplementation with progesterone and the oral progestogen dydrogesterone, as well as the progesterone-induced blocking factor in the prevention and/or treatment of these serious complications.

Association Between Maternal Hormonal Contraception Use and Central Nervous System Tumors in Children

The incidence of central nervous system (CNS) tumors in children appears to be increasing, yet few risk factors are established. There is limited information regarding whether maternal hormonal contraception use increases this risk. To examine the association between maternal hormonal contraception use and CNS tumors in children (<20 years). In this nationwide cohort study based on population-based registry data, 1 185 063 children born in Denmark between January 1, 1996, and December 31, 2014, were followed up for a diagnosis of a CNS tumor (final follow-up on December 31, 2018). Maternal hormonal contraception use was analyzed according to any use, regimen (combined/progestin only), and route of administration (oral/nonoral), categorized as recent use (≤3 months before start and during pregnancy), previous use (>3 months before start of pregnancy), and no use. For injections, implants, and intrauterine devices that are used for a different time period, the categorization was appropriately altered. Hazard ratio (HR) and incidence rate difference (IRD) of CNS tumors diagnosed at younger than 20 years. After 15 335 990 person-years of follow-up (mean follow-up, 12.9 years), 725 children were diagnosed with a CNS tumor. The mean age at diagnosis was 7 years, and 342 (47.2%) of the diagnosed children were female. The adjusted incidence rate of CNS tumors per 100 000 person-years was 5.0 for children born to mothers with recent hormonal contraception use (n = 136 022), 4.5 for children born to mothers with previous use (n = 778 843), and 5.3 for children born to mothers with no use (n = 270 198). The corresponding HRs were 0.95 ([95% CI, 0.74-1.23]; 84 children with CNS tumors; IRD, -0.3 [95% CI, -1.6 to 1.0]) for recent use and 0.86 ([95% CI, 0.72-1.02]; 421 children with CNS tumors; IRD, -0.8 [95% CI, -1.7 to 0.0]) for previous use, compared with no use. No statistically significant associations were found for recent or previous use of oral combined, nonoral combined, oral progestin only, or nonoral products compared with no use of hormonal contraception. Among Danish children, there was no statistically significant association between any maternal hormonal contraception use and CNS tumor risk.

Risks and Benefits of HRT Versus ERT in Order to Separate HRT from ERT

Aim: While the benefits of Hormone Replace Therapy (HRT) and Estrogen Replace Therapy (ERT) might overlap, their risks have to be separated particularly with regard to breast cancer. The risks of HRT are mainly Coronary Heart Disease (CHD) and Breast cancer. The main risk of ERT is the incidence of strokes which can be avoided by not using an oral estrogen but an Intra-uterine contraceptive but reducing the risk of endometrial cancer in women with a womb. Methods: Studies that randomized peri-menopausal and menopausal women to either HRT or ERT versus placebo and one study that included similar women followed up prospectively for the incidence of the development of Alzheimer’s Dementia (AD). Results: The significant risks of HRT included CHD, stroke and pulmonary embolism. The risk of breast cancer only really existed after long term follow-up [(annualized incidence, 0.45% vs 0.36%; Hazard Ratio (HR) 1.28)]. The significant risks of ERT only included strokes. There was a lower risk of breast cancer in the long term [HR 0.77, 95% CI 0.62–0.95; p=0.02]. Conclusions: In women with a uterus, where HRT instead of ERT is mandated, the oral progestogen of HRT can be replaced by intrauterine device loaded with a Progestogen. Similarly, the oral Estrogen of HRT and ERT can be replaced by Estrogen sources like the patch, gel or implants that bypass the liver and bypass potential problems like strokes and pulmonary embolism.

Progestin-Primed Ovarian Stimulation is a non-inferior alternative to the GnRH Antagonist Protocol in patients undergoing assisted reproductive techniques: a retrospective study.

Objective To demonstrate the non-inferiority of Clinical Pregnancy Rates from Progestin-Primed Ovarian Stimulation compared to the GnRH Antagonist Protocol when the freeze-all and blastocyst transfer strategy is applied.Methods A retrospective study included all IVF cycles performed at Pró-Criar Reproductive Medicine Center, Belo Horizonte, Minas Gerais, Brazil, between May 2018 and May 2019 using a GnRH antagonist analogue or oral progestins to block the LH peak in IVF/intra-cytoplasmic sperm injection (ICSI) cycles for infertility treatment.Results The primary outcome of our study was Clinical Pregnancy Rate at the first ET (Blastocyst), which were 58.4% in the progestin group and 54.9% in the antagonist group (p=0.735), a finding consistent with most studies published to date using different progestins. The mean number of retrieved oocytes was 11 in the antagonist group and 9 oocytes in the progestin group (p=0.009). The fertilization rate was 80% for both groups (p=0.935). The rate of blastocyst formation per cycle was 50% in the antagonist group and 55.6% in the progestin group (p=0.106). The stimulation lasted a mean of 10 days in the two groups (p=0.403) and did not vary with patient age in either group. The gonadotropin dose used was higher in the antagonist group (2025 IU) than in the progestin group (1950 IU) (p=0.057). In addition, the blockade was effective: there was only one case of spontaneous ovulation, which corresponded to less than 1% of the cycles.Conclusions Progestin-Primed Ovarian Stimulation is a non-inferior alternative to the GnRH Antagonist Protocol in patients undergoing assisted reproductive techniques. An incidence compatible with the 0.34 to 8% risk described in the literature for failure to control the premature LH surge in antagonist protocol cycles.

Conservative Surgery in Endometrial Cancer

Endometrial cancer (EC) is the sixth most common female cancer worldwide. The median age of diagnosis is 65 years. However, 4% of women diagnosed with EC are younger than 40 years old, and 70% of these women are nulliparous. These data highlight the importance of preserving fertility in these patients, at a time when the average age of the first pregnancy is significantly delayed and is now firmly established at over 30 years of age. National Comprehensive Cancer Network (NCCN guidelines state that the primary treatment of endometrial endometrioid carcinoma, limited to the uterus, is a total hysterectomy, bilateral salpingo-oophorectomy and surgical staging. Fertility-sparing treatment is not the standard of care, and patients eligible for this treatment always have to undergo strict counselling. Nowadays, a combined approach consisting of hysteroscopic resection, followed by oral or intrauterine-released progestins, has been reported to be an effective fertility-sparing option. Hysteroscopic resection followed by progestins achieved a complete response rate of 95.3% with a recurrence rate of 14.1%. The pregnancy rate in women undergoing fertility-sparing treatment is 47.8%, but rises to 93.3% when only considering women who tried to conceive during the study period. The aim of the present review is to provide a literature overview reflecting the current state of fertility-sparing options for the management of EC, specific criteria for considering such options, their limits, the implications for reproductive outcomes and the latest research trends in this direction.

Fertility-preserving treatment in patients with early-stage endometrial cancer

Background:Endometrial cancer (EC) is the second most common malignancy of the female reproductive system worldwide, and the standard treatment for early-stage EC potentially leads to permanent infertility. The objective of this study was to investigate the efficacies of different methods on fertility preservation in patients with early-stage EC.Methods:We searched the major online databases (PubMed, Embase, The Cochrane Library, and Web of Science) to collect the research literature on fertility preservation therapy in patients with early-stage well-differentiated EC aged ≤ 40 years from January 1999 to October 2019. The inclusion was performed using the R software (version R3.5.3) meta-analysis of a single rate. The efficacy of the following three fertility preservation treatments was evaluated from four aspects, the complete remission rate (CRR), recurrence rate (ReR), pregnancy rate (PregR), and live birth rate (LBR): a) taking oral progestin only therapy, b) hysteroscopic resection combined with progestin/levonorgestrel-releasing intrauterine system (LNG-IUS)/GnRH-a, c) LNG-IUS or combined with progestin/GnRH-a.Results:A total of 23 articles were included in this study, including 446 patients with early-stage EC. In the group that took oral progestin only (n = 279), CRR, ReR, PregR, and LBR were 82% (95% confidence interval [CI], 74%–92%, P = .01), 38% (95% CI, 31%-45%, P = .35), 70% (95% CI, 62%–79%, P = .68), and 63% (95% CI, 55%–73%, P = .55), respectively. Hysteroscopic resection combined with progestin/LNG-IUS/GnRH-a therapy group (n = 96) achieved a CRR, ReR, PregR, and LBR of 95% (95% CI, 90%–100%, P = .42), 16% (95% CI, 6%–39%, P = .03), 84% (95% CI, 73%–96%, P = .39), and 72% (95% CI, 59%–87%, P = .28), respectively. LNG-IUS or combined with progestin/GnRH-a therapy group (n = 91) achieved a CRR, ReR, PregR, and LBR of 69% (95% CI, 54%–89%, P < .01), 30% (95% CI, 19%–49%, P = .36), 48% (95% CI, 18%–100%, P < .01), and 36% (95% CI, 10%–100%, P < .01), respectively.Conclusion:It is safe and effective for young patients with early-stage EC to receive oral progestin, hysteroscopic resection combined with progestin/LNG-IUS/GnRH-a, LNG-IUS, or progestin/GnRH-a.INPLASY Registration number:DOI 10.37766/inplasy2020.12.0137